Polynuclear cyclic oxyketones and derivatives thereof and process of making same



Patented Jan. 19, 1943 POLYNUCLEAR GYCLIG OXYKETONES AND DERIVATIVES THEREOF AND PROCESS OF MAKING SAME Leopold Ruzicka, Zurich, and AlbertWettstein,

Basel, Switzerland, assignors, by mesne assignments, to Ciba Pharmaceutical Products, Incorporated, Summit, N.

Jersey J., a corporation of New No Drawing. Original application Julie 15, 1936, Serial No. 85,437. Divided and this application August 16, 1937, Serial No. 159,432. In Switzerland June 18, 1935 21 Claims. (01. too-397.4)

The present application is a division otapplicants prior application Ser. No. 85,437, filed June Isomeric oxyketones of the saturated or unsaturated androstane-series, whose hydroxyl and keto-groups in comparison with the compounds of the androsterone series are interchanged, are not yet known.

This invention is based on the observation that such new oxyketones and their esters are obtainable by partially saponifying a di-ester of a diol of the type of the saturated or unsaturated androstane diols-(3:17), oxidizing the free carbinol-group (in 3-position) thus produced (if necessary with temporary protection of the double bonds present) to a keto-grou'p and, if desired, purifying and saponifying the keto-ester thus obtained.

A particularly advantageous procedure consists in-starting from a mixed di-ester of a diol of the type of the saturated or unsaturated androstane-diols, particularly those esters in which the hydroxyl group in 3-position is esterified with an acid radical which is comparatively easily saponifiable, whilst that in 17-position is esterified by an acid radical which is saponifiable with comparative difiiculty. One can also start from a free diol, partially esterify this and oxidise the resulting diol, mono-esterified in 17-position,

' in the manner described above, advantageously after purification.

The same oxyketone can be produced by subjecting the free diol, if desired with temporary protection of double bonds present, directly to a partial oxidation and separating from the reaction product the compound which has undergone oxidation at the 3-position.

Finally, it is also possible to obtain those new oxyketonesby subjecting to' a partial reduction a diketone of the type of the androstane-dione- (3:17) and separating from the reduction product the 3-keto-l7-oxy-compound.

The carbinol-group in 3-position can also be oxidized to a keto-group by the action of a dehydrogenating agent.

The various methods may be illustrated by the following formulae, in which AC1 and Ac: mean the same or different acyl radicals and R represents hydrogen or a monovalent hydrocarbon radical:

o i to o v) H sci-o H0 1 partial saponitication l %irtiai csteritlcatlon CH; CH;

x/ mo- V R ic.

HO gonatlon 0N III IV'- esteriflcationsaponiflcation CH3 Clix R p 'OH VII partial oxidation 7 or dehydrogenatiy partial reduction CH3 OH: R CH; CH;

1 I F H l l HO V 0/ V VI into IV or for converting V into VII there may be used, for example, a hexavalent chromium compound such as chromic acid in glacial acetic acid; furthermore copper oxide and the like. In the oxidation of an unsaturated diol or its ester to an oxyketone or its ester the carbon double linkage is advantageously protected from the action of the oxidizing agent, for example by the attachment of halogen or hydrogen halide; after oxidation the halogen is then again removed, for example by treatment with zinc in glacial acetic acid or benzene, with catalytically activated hydrogen or with an alkali iodide, or the hydrogen halide is again removed by treatment with an alkaline agent such as a tertiary base. The conversion, of the free diols into 3-keto-17-oxycompounds'by oxidation of the 3-carbinol-group proceeds in a particularly advantageous manner in cases in which the nuclear carbon atom in l'l-position is linked to a hydrocarbon radical.

When a mixed di-ester is to be subjected to partial saponiflcation' there are advantageously usedthose which contain in 3-position the radical of a lower fattyacid suchas acetic acid or formic acid, and in l'l-position the radical of a higher fatty acid such as a valeric acid, or'a carbamic acid, benzoic acid, a toluic acid, hexahydrobenzoic acid or a hydrohalogen acid.

The aforesaid mixed di-esters are obtained by causing to act on a 3-mono-ester of a dial of the type of the saturated or unsaturated androstane diols an acylating agent containing an acid radical difierent-from that already present in the molecule of the mono-ester.

The partial saponiflcation may be conducted, for example, in methyl alcohol, ethyl alcohol, in a higher alcohol, in dloxane, acetone or-the like. If an alcohol is used re-esteriflcation generally occurs'in, addition to the actual saponiflcation, so that the quantity of alkali solution consumed is frequently considerably less than the calculated quantity. Oneis therefore not restricted to the use of the calculated quantity of alkali, but may use a larger or a smaller quantity. By this means, as well as by the concentration of the alkali solution and the temperature, the izluration of the reaction maybe favorably influenced.

Suitable acylating agents for converting II into III and for converting VII into IV are, for instance, acids, acid halides and acid anhydrides, for example benzoic' acid, acetic acid, formic acid, benzoyl chloride, acetyl chloride, acetic anhydride and the like, if required in the presence of an acid binding agent such as a tertiary base or an alkali. Particularly when an acid halide or an acid anhydride is used there is advantageously taken for the partial esteriflcation of II only a quantity of acylating agent sufficient for esterifying one hydroxyl-group'.

In the partial reduction of VI the hydrogenato the keto-group there may be used with advantage any of the usual dehydrogenating agents,

for instance selenium, sulfur, or a metalliccatalyst belonging to the group of hydrogenating or dehydrogenating catalysts such as copper, platinum, palladium, gold, nickel and the like, if

desired in the presence of a hydrogen acceptor such as naphthalene, phenol, fumaric acid or the like.

It (is easily possible to cynnamic acid,

isolate in a pure form As suitable oxidizing agents for converting III the oxyketone produced either by direct crystaliization or by preparing a suitable derivative. Such derivatives are obtained, for example, by reaction with the usual ketone reagents such as 5 semi-carbazide, I thiosemicarbazide, hydroxylamine, aminoguanidine, phenylhydrazine and its substitution products, neutral or basic acylhy drazides. For purification and separation acyla- I tion is often useful, for example by means of acetic anhydride, benzoyl chloride, dinitro-ben- ,zoyl chloride or the like. By the action of hydrolytically acting agentsthe i above. compounds can be split into their components. For separating the 3-keto-compound from any 3-oxycompound which may have been formed as a byproduct there have been proved advantageous or aryl-group; so also the scope of the 3:17-

androstane-diones extends also to the isomeric 3:17-aetiocholanediones; The following -diols, for example, are suitable parent materials for the invention: the androstane-diols-(3:17), the A or A -androstene-diols-(iizll), the 1'!- methylor :17-ethyl-androstane-diols-(3: 17) the 1'7-methyl-- or l'l-ethyl-androstene-diols- 3 17) in which in each case the carbinol-groups in both 3- and l'l-positions may be in 'cis-, or

epi-, or in trans-position. Suitable parent materials of the dione-series areamong others the 49 androstane-dione-wzl'm the A ='.-androstenedione-(3:l7) and the aetIochoIane-dione-(SH'I) The new oxy-ketones as well as their esters have powerful eil'ects on the combs of capons and also on the seminal vesicle. Q

The following examples illustrate the invention:

Example 1 3.76 7 grams of androstane-diol-(3,1'l) -d iacetate of the formula on. on.

H. '-o.co.cn=

K I l I outcrop V of melting point 127-128 0. are allowed to stand for 48 hours at room temperature in 1000 cc. of n/lOO-methyl-alcoholic potash solution. After concentrating the solution, the 17-acetoxyandrostane-ol-(3), produced by the partial 'saponification, is precipitated by addition of water, filtered, washed with water and dried in a vacuum over phosphorus pentoxide. It may be used without further purification for making androstane-ol-(l'l) -one-(3). For this purpose the product is dissolved in 50 cc. of glacial acetic acid and-there is added, while cooling,,a solution of 0.8 gram of chromium trioxlde in 25 cc. of acetic acid of per cent. strength. After standing for 14 hours at room temperature some methanol is added for' the purpose of reducing the small excess of chromic acid. The solution CH: cHr I I By recrystallization from hexane or dilute a1- cohol the latter may be purified. It forms colorless crystals of melting point 182 C.

In like manner there may also be obtained the propionate of melting point 121-122 C. or the n-butyrate of melting point 90.5-91.5 C.

Example 2 3.74 grams of A "-androstene-diol-(3z17)ediacetate of the formula CH1 CH8 H O.CO.CH9

CH:.C0.0

of melting point 165-166 0., in which the two hydroxyl groups are probably in trans-configuration, are allowed to stand at room temperature for 40 hours in 1000 cc. of methyl alcohol to which have been added previously 0.45 gram of potassium hydroxide. After neutralizing, the solution is strongly concentrated in a vacuum and then the crude A -17-acetoxy-androstene-ol- (3), which has been produced by partial saponification, is precipitated by addition of water, extracted with ether and obtained by evaporation of the ether. The crude monoester thus obtained is purified by recrystallization from hexane, with removal of sparingly soluble constituents and the purified ester of melting point 146-148 C. is taken up in 50 cc. of glacial acetic acid and, while cooling, there is added, drop by drop, a solution of bromine in glacial acetic acid as long as there is immediate decolorization. Finally, also in the cold, there is added 1 gram of chrominum trioxide dissolved in 30 cc. of acetic acid of 90' per cent. strength and the whole is allowed to stand over-night at room temperature. The whole is then poured into 1 liter of water, the precipitated product is filtered and washed with much water. The brominated ketone thus obtained is dissolved for the purpose of debrominating it in 50 cc. of glacialacetic acid, and after addition of 20 grams of zinc dust the whole is heated while vigorously shaking for 12 minutes on the boiling water-bath. There follow filtration through a glass filter, washing with a little hot glacial acetic acid, precipitating the solution with water and extraction with ether. The ethereal solution is washed with dilute sodium carbonate solution and water andthen evaporated to yield a residue,

from which A -androstene-ol--(1'I) -one-(3)- acetate may be isolated by means of its semicar- 5 bazone, and after recrystallization from hexane melts at 141 C. By saponiflcation it may be converted into the free oxyketone, namely A" androstene-o1-(1'7)-one-(3) of the formula CHI which melts at 155 C. When using other esters,

there are obtained the corresponding keto-esters in an analogous manner, for instance A androstene-ol-(17)-one (3) benzoate of melting point 194195 C.

The propionate of melting point; 121-123 The n-butyrate of melting point 111-113 The iso-butyrate of melting point 131-133 The n-valerianate of melting point 109-111 The n-caprinate of melting point 55- 57 The palmitate of melting point 72- 74 o The stearate of melting point 79- 80 which esters may be saponified, if desired.

The double linkage may be protected by chlorine, for example, instead of bromine.

Example 3 1.87 grams of A -3-trans-17-cis-androstenediol-diacetate of the formula C H; CH;

of melting point 168 C. are dissolved in 370 cc. of methanol and the solution is mixed with a solution of 0.28 gram of potassium hydroxide in a small quantity of methanol. The whole is allowed to stand at 15 C. for 36 hours, whereupon it is exactly neutralized with dilute hydrochloric acid, and the solution is concentrated in a vacuum to cc. It is then diluted with water and the reaction product is taken up in ether and the ethereal solution is dried and evaporated. By fractionally crystallizing the residue from hexane, the l7-mono-acetate of A -3-trans-17- in 30 cc. of glacial acetic acid and treated with the calculated quantity (1 mol) of bromine in glacial acetic acid. The bromine is immediately decolorizedl There is then added a' solution of 1 mol of chromic acid in acetic acid of 90 per cent. strength and the whole is allowed to stand over-night at room temperature. The reaction product is then precipitated by addition of water, filtered, debrominated by shaking in an alcoholic solution for 48 hours with zinc dust and finally purified by recrystallization from hexane. From the acetate of A -androstene-cis-ol-(17) -one- (3) of melting point 115 C. there is obtained by saponification with methyl alcoholic potash of cis-androstene-diol is obtained. This is dissolved 2 per cent. strength the A -androstene-cis-ol- (17) -one-(3) of the formula AW w - of melting point 200-221 C.

Example 4 2.31 grams of A ='-3-trans-17-trans-andr0stene-diol-3-actate-1'l-benzoate of the formula CH: OH: H

"0.00.0111 H l CHaCbDx/V of melting point 178-180 C. are mixed with 500 cc. of methyl alcohol. .The mixture is stirred for a long time (about 50hours) at room temperature and there is added, gradually by drops, a methyl alcoholic solution of 0.3 gram of potassium hydroxide. After neutralization the whole is highly concentrated in a vacuum; the crude product is precipitated by the addition of water, extracted by means of ether and the ethereal solution is evaporated. The residue is crystallized from hexane, yielding brilliant needles of melting point 222-223" C. of the A5 =-3-trans-1'ltrans-androstene-diol-l'l benzoate.

This mono-ester is dissolved in 50 cc. of glacial acetic acid and there is added, while cooling and in drops, the calculated proportion of a solution ofbromine in glacial acetic acid. Finally, 0.5 gram of chromium trioxide dissolved in cc. of acetic acid of 90 per cent. strength is added in the cold and the whole is allowed to stand over-night at room temperature, during which time the oxidation product in part crystallizes. The mass is then poured into water, the precipitated matter filtered and washedwith much water. The brominated ketone thus obtained is debrominated by. violent agitation with zinc dust in glacial acetic acid on the boiling water-bath. The mass is then filtered, washed and the solution precipitated by means of water. The precipitate is extracted with ether, the ethereal solution shaken with dilutev sodium carbonate solution andwater and evaporated. It is also possible to debrominate the brominated ketone by heating a dry solution of it in benzene with an alcoholic solution of sodium iodide. In this case the solution is subsequently washed with aqueous sodium sulfite solution and water and evaporated. 7

From the crude product made by one or the other of these methods may be obtained, for instance by recrystallizing it from hexane or by sublimation in a high vacuum or by both methods, or by means of the sparingly soluble semicarbazone, the A -androstene-trans-ol-(17) one-(3) -benzoate of melting. point 193-194. C. By saponifieation with alcoholic potash this benzoate may be converted into the freeoxyketone, namely A -androstene-trans-ol-(17)-one-(3)- 5 of the formula 0H1 cm Example 5 Into 1 liter of ethyl alcohol which has been preheated to C. there are introduced first 5 grams of A --androstene-3 17-diol-3-acetatel'l-benzoate of the formula CH: C Hi of melting point FIB-180 C. and then one molecular proportion of an ethyl alcoholic potash solution (containing 0.64 gram of potassium hydroxide) and the whole is thoroughly stirred for! hours at the aforesaid temperature. The solution is neutralized (the quantityof alkali consumed amounting to about 10 per cent.) and then highly concentrated in a vacuum and the crude product is shaken with water and ether, the ethereal solution is separated and evaporated. By crystallizing the residue from isopropyl ether A -androstene-3:17-diol-17-benzoate is tained in the form of brilliant needles of melting point 222-223 C,

This mono-ester is oxidized with chromic acid, after bromination in glacial acetic acid, in a manner analogous to that described in Example 2. For debrominating the brominated ketone thus obtained the ketone is dissolved in benzene, the solution is carefully dried and then boiled for 3 hours in a reflux apparatus together with a solution of sodium iodide in absolute alcohol.

sulfite solution of 2per cent. strength,'the benzene layer which separates is removed, shaken further with a sodium sulflte. solution and with a bicarbonate solution 'and then evaporated. It

is also possible to debrominate the brominated ketone, for example, by the action of zinc in glacial acetic acid or in a mixture of benzene and alcohol. In these cases the reaction mixture is filtered, the filtrate is mixed with water and ether and after separation into layers the In a similar manner by partial saponiflcation The reaction-mixture is poured into a sodium upper layer is washed with a dilute sodium carbonate solution and with waterand then evaporated. The crude A -GIIdI'OStGHB-3-DIIBe17-Olbenzoate of the formula CH: OH: H

thus obtained may be purified just as described in Example 4.

In comparison with the use of a methyl alcoholic potash solution the use of anethyl alcoholic potash solution considerably shortens the duration of the reaction. Propyl, butyl and amyl alcohols have also provedadvantageous in this respect.

Example 6 H I l of melting point 223 C. are heated in 100 cc. of acetic acid of '90 per cent. strength for 8 hours on the water-bath, and then allowed to stand overnight at room temperature. The reaction product is precipitated with water, pressed and dried in a vacuum over phosphorus pentoxide. By systematically treating it with benzine (boiling range 70-80 C.) it is separated into sparingly soluble and more easily soluble fractions. The sparingly soluble fraction is unchanged diol. By recrystallization of the more easily soluble fraction from dilute alcohol there is obtained the 17- mono-acetate of androstane-diol-(3:17) which melts at 192 C. This ester is oxidized in the manner described in Example 1, and if required the oxidation product is saponified to yield androstane-ol-(1'7) -one-(3) of the formula CH3 CH3 of melting point 182 C.

Example 7 2.9 grams of A -androstene-diol-(3:17) of the formula CH; CH: I

acetyl chloride are brought to reaction in pyridine. The reaction mixture is poured into wa- ,ter, the pyridine is neutralized by addition of an acid, the precipitated crude product is extracted with ether and the ethereal solution is washed and evaporated. Fractional crystallization of the res- 5 idue from hexane yields pure A 17-acetoxyandrostene-ol-(El) of melting point 146-148 C. The mono-ester so obtained is brominated, oxidized with chromic acid in glacial acetic acid and debromiriated with zinc dust and acetic acid in the 10 manner described in Example 2, whereby there is obtained, the keto-ester, namely A -androstene-ol-(l'l) -one-(3) -acetate of melting point 141 C., which if required can be converted by saponification into the A -androstene-ol-(17)- one-(3) of the formula CH3 I CHI H \J k/\J of melting point 155 C.

In an analogous manner by partial benzoylation instead of acetylation A -androstene-rliol- (3:17) can be converted by way of its 17-monobenzoate of melting point 222-223 G. into the A -androstene-ol-(17) one (3) benzoate of melting point 194-195 C.; if required the latter can be converted by saponification into the above described A -androsteneol- (17) -one- (3) of melting point 155- C.

Example 8 2 grams of A -androstene-3:17-diol-17-benzoate of the formula of melting point 222-223 C., obtainable as an intermediate product in the processes of Examples 4, 5 and '7, and 2 grams of copper powder are heated'at 225 C. in a vacuum until evolution of gas has ceased. The mass is then treated with 20 cc. of alcohol, the solution filtered, the solid matter washed and the filtrate is poured into 200 cc. of water and extracted with ether.

The ethereal solution is washed with sodium carbonate solution and water and evaporated. From the residue the A -androstene-ol-(l7)- one-(3) -benzoate of melting point 193494: C. is isolated, for example by re-crystallization from isopropyl ether and/or sublimation in a high vacuum or by conversion into its sparingly soluble semicarbazone. By saponification with alcoholic alkali solution the 'benzoate is converted into the free oxy-ketone, namely A -and.ro-

5 stene-ol-(l7)-one-(3) of the formula om cm OH A I of melting point C.

Example 9 2 grams of androstane-3:17-diol-17-acetate of the formula CH: C H

' o.oo.cm

fl W of melting point 192 0., obtainable as an intermediate product in the process of Examples 1 and 6, and 2 grams of cinnaniic acid are dissolved in 100 cc. of glacial acetic acid and the solution is shaken while warm with a palladium catalyst, When the reaction is at an end the catalyst is filtered and the filtrate is poured into 800 cc. of water and the liquid is extracted with ether. The etherea solution is washed with water, dried and evaporated in a vacuum. The residue is saponified while warm with alcoholic alkali solution of 2 per cent. strength and the saponification mixture is poured into water and the whole extracted with ether. The ethereal solution is washed repeatedly with sodium carbonate solution and then with water, whereafter it is evaporated in a vacuum. From the residue androstaneol-(l7)-one(3) of the formula on, om

L fi of melting point 182 C. is obtained, for example .by recrystallization and/or sublimation in a high 3.06 grams of 17 methyl androstane' diol- (3:17) of the formula of melting point 185 C. are dissolved in 50 cc. of glacial acetic acid and, at room temperature, there is added in drops a solution of 0.8 gram of chromium trioxide in 50 cc. of glacial acetic. acid. The chromic acid is somewhat rapidly consumed; the whole is allowed to stand for 3 hours at room temperature, then poured into water and the product thus precipitated is dissolved in ether. The ethereal solution is washed with dilute caustic soda solutiomand water and dried over anhydrous sodium sulfate. From the strongly concentrated ethereal solution the l'l-methyl- Oil).

crystallizes. By recrystallization from dilute alcohol it is purified and then melts at 192 C.

I The semicarbazone obtained in the usualmanner tained the l 'l-ethyl-androstane-ol-(17) -one-(3) of melting point 126-127 C. and from 3-trans-.

or 3-cis-1"l-trans-androstane-diolsthe androstane-ol-(l'Zl-one-(Zi) of melting point 182 C.

The reaction proceeds in analogous manner with compounds containing in the l'l-position a substituted hydroxyl group, such as an acyloxy- ,or an alkoxy-group.

Example 11 3.04 grams of A -l'l-methyi-androstene-diol- (3:17) of the formula.

' om cm .el/Q

of melting point 202-204" C. are dissolved in 50 cc. of glacial acetic acid and mixed with a solution of 1.6 grams of bromine in 10 cc. of glacial acetic acid. To this solution there is added, by

drops, one of 0.8 gram of chromium trioxide in 50 cc. of glacial acetic acid. After severalhours' standing at room temperature the whole is poured into water, the precipitated dibromide is'filtered, washed and treated in glacial acetic acid solution with 3 grams of zinc dust. The filtered solution is then poured into water and the precipis dissolved in ether. The washed and dried ethereal solution is evaporated and the residue recrystallized from dilute alcohol, Its melting point lies at 161162 C.

Instead of glacial acetic acid, benzene for example may be used as solvent-- for the debromination.

In a similar manner A: androstene-ol-(17) one-(3) of melting point 155 C. can be obtained from A -androstene-diol-(3z17) of melt Point 182l83 C.

One may also start from compounds which are acylated in 17'-position or substituted in another manner.

Example 12 2.88 grams of androstane-dione-(3:17) of the formula.

on; I'CH:

of melting point 134 C. are dissolved in 30 cc. of methyl alcohol and into this solution there is gradually introduced, at boiling temperature, the calculated quantity of sodium. When reduction is complete a precipitate is produced by pouring the mass into water; this is then filtered, washed with much water and dried over phosphorus pentoxide. This product is a mixture of isomeric androstane-ol-ones. The androstane-ol-(1'7)-one-(3) of the formula OH: H

tion.

Example 13 2.86 gramsof A -androstene-dione-(3:1'7) of the formula k on; om

of melting point 173-174 Q. are dissolved in alcohol and hydrogenated with the'aid of a nickel catalyst. When the amount of hydrogen calculated for one molecule has been absorbed, hydrogenation is interrupted, the catalyst is filtered from the solution, and the latter ispoured into 400 cc. of water. The mass is extracted with ether and the ethereal solution is washed with water and evaporated in a vacuum. The residue is esterifled by heating for a short time with a fewcc. of acetic anhydride; the latter is then evaporated and the residue fractionally crystallized from dilute acetone. In this manner one obtains the A -androstene-ol- (17) -one-(3) acetate of melting point 141 C. By saponiiication the corresponding free oxy-ketone is produced, namely A -androstene-o1- (17) -one-(3) of the formula of melting point 155 C;

hydroxyl group in the 17-position of a diol of the formula CH3 cm H I OH Ha'VJ and then oxidizing thefree carbinol to a keto group, I

' 3. A process for the manufacture of a compound of the cyclopentanopolyhydrophenanthrene series, comprising first acylating the hydroxyl group in the l7-po'sition of a'diol of the formula CH1 CH3 H Al I y ()H k V H l V oxidizing the free carbinol to a keto group, and hydrolizing the acylated hydroxyl group.

4. A process as claimed in claim 3, wherein" there is used an acetylating agent for the acylation.

5. A process for the manufacture of a compound of the cyclopentanopolyhydrophenan-.

threne series, comprising first acylating the hydroxyl group in the l'l-position of a did of the formula CH: oH

Babe

and then oxidizing the free carbinol to a keto group.

6. A process for the manufacture of a compound of the cyclopentanopolyhydrophenanthrene series, comprising first acylating the hydroxyl group in the 17-position of a diol of the formula Olly/x0711: T on AN H I no and then oxidizing the free carbinol to a keto group with temporary protection or the carbon double bond present.

7. A process for the manufacture of a compound of the cyclopentanopolyhydrophenan-' threne series, comprising first acylating the hydroxyl group in the l7-position of a diol of the formula CH; OH:

oxidizing the free carbinol to a keto group with temporary protection of the carbon double bond present, and hydrolizing the benzoylated hydroxyl group.

10. A process for the manufacture of a .compound oi the cyclopentanopolyhydrophenanthrene series, comprising first reacting a benzoylating agent in molecular proportions with the hydroxyl group in the 17-position of a diol of the formula CH1 CH1 oxidizing the free carbinol to a keto group with I temporary protection of the carbon double bond present, and hydrolizing the benz'oylated hydroxyl group.

11. A manufacture as claimed in claim of a tertiary base.

12. The saturated 3-keto-10,13-dimethy1cyc1opentanopolyhydrophenanthrenes containing in the 1'7-position the group CH-R, wherein R is a member 01 the group consisting of a tree, esterified and etherifled hydroxyl.

- '13. The compounds of the formula on; on.

. ijll) wherein R is a member of the group consisting of .a free, mterifled and etherified hydroxyl.

14. The compound of the formula forming colorless crystals of melting point 182 C.

15. The compounds of the formula CH: CH:

wherein Ac stands for an acyl group.

16. The compound of the formula CH; CH

/ of melting point 121-122.c.

17. The compound of the formula CH3 CH3 H of melting point 90.5-91.5 0.

18. A process for the manufacture of a compound of the 10,13-dimethylcyclopentanopolyhy- 10, wherein the-benzoylation is effected in presence drophenanthrene series, comprising oxidizing the 3-carbinol group, of a 10,13-dimethy1cyc1opentanopolyhydrophenanthrene-3,1'7-diol to a keto group after replacement of the hydroxyl group in the 17-position by a group which can be converted into the hydroxyl group with. the aid of hydrolysis.

19. The compounds of the formula. 20. The compound of the formula on; on, H 11 I -LOH 5 A U 041 J m AN 21. The acetate 01 androstano1-17-one-3. wherein R is a group which can be converted in LEOPOLD RUZICKA.

OH with the aid 01. hydrolysis. ALBERT WETISTEIN. 

